Lygate Craig A, Lake Hannah A, McAndrew Debra J, Neubauer Stefan, Zervou Sevasti
Division of Cardiovascular Medicine, Radcliffe Department of Medicine and British Heart Foundation Centre for Research Excellence, University of Oxford, Oxford, United Kingdom.
Front Nutr. 2022 Aug 9;9:969702. doi: 10.3389/fnut.2022.969702. eCollection 2022.
Organisms obtain creatine from their diet or by synthesis AGAT (L-arginine:glycine amidinotransferase) and GAMT (Guanidinoacetate N-methyltrasferase) in kidney and liver, respectively. AGAT also synthesizes homoarginine (hArg), low levels of which predict poor outcomes in human cardiovascular disease, while supplementation maintains contractility in murine heart failure. However, the expression pattern of AGAT has not been systematically studied in mouse tissues and nothing is known about potential feedback interactions between creatine and hArg. Herein, we show that C57BL/6J mice express AGAT and GAMT in kidney and liver respectively, whereas pancreas was the only organ to express appreciable levels of both enzymes, but no detectable transmembrane creatine transporter (). In contrast, kidney, left ventricle (LV), skeletal muscle and brown adipose tissue must rely on creatine transporter for uptake, since biosynthetic enzymes are not expressed. The effects of creatine and hArg supplementation were then tested in wild-type and AGAT knockout mice. Homoarginine did not alter creatine accumulation in plasma, LV or kidney, whereas in pancreas from AGAT KO, the addition of hArg resulted in higher levels of tissue creatine than creatine-supplementation alone ( < 0.05). AGAT protein expression in kidney was downregulated by creatine supplementation ( < 0.05), consistent with previous reports of end-product repression. For the first time, we show that hArg supplementation causes a similar down-regulation of AGAT protein ( < 0.05). These effects on AGAT were absent in the pancreas, suggesting organ specific mechanisms of regulation. These findings highlight the potential for interactions between creatine and hArg that may have implications for the use of dietary supplements and other therapeutic interventions.
生物体从饮食中获取肌酸，或通过分别在肾脏和肝脏中合成AGAT（L-精氨酸：甘氨酸脒基转移酶）和GAMT（胍基乙酸N-甲基转移酶）来获取。AGAT还能合成高瓜氨酸（hArg），其低水平预示着人类心血管疾病的不良预后，而补充高瓜氨酸可维持小鼠心力衰竭时的心肌收缩力。然而，AGAT在小鼠组织中的表达模式尚未得到系统研究，关于肌酸和高瓜氨酸之间潜在的反馈相互作用也一无所知。在此，我们表明C57BL/6J小鼠在肾脏和肝脏中分别表达AGAT和GAMT，而胰腺是唯一表达这两种酶且水平可观的器官，但未检测到跨膜肌酸转运蛋白（）。相比之下，肾脏、左心室（LV）、骨骼肌和棕色脂肪组织必须依靠肌酸转运蛋白来摄取肌酸，因为它们不表达生物合成酶。然后在野生型和AGAT基因敲除小鼠中测试了补充肌酸和高瓜氨酸的效果。高瓜氨酸并未改变血浆、左心室或肾脏中的肌酸积累，而在AGAT基因敲除小鼠的胰腺中，添加高瓜氨酸导致组织肌酸水平高于单独补充肌酸（<0.05）。补充肌酸可下调肾脏中AGAT蛋白的表达（<0.05），这与之前关于终产物抑制的报道一致。我们首次表明，补充高瓜氨酸会导致AGAT蛋白出现类似的下调（<0.05）。胰腺中未出现这些对AGAT的影响，表明存在器官特异性调节机制。这些发现突出了肌酸和高瓜氨酸之间相互作用的可能性，这可能对膳食补充剂的使用和其他治疗干预措施具有重要意义。
